Composition comprising an amorphous non-crystalline glass form of azithromycin

ABSTRACT

The invention relates to an amorphous non-crystalline glass form (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside or azithromycin having an infra-red pattern displaying characteristic relatively broad peaks at approximately 3500 and 1727 cm −1  and characteristic peaks at approximately 2970 and 2938 cm −1 . The invention further relates to a preparation method of increasing the solubility of azithromycin including the steps of selecting anhydrous, monohydrated or dihydrated azithromycin; elevating the temperature of the azithromycin to above the melting point thereof; and reducing the temperature of the melt sufficiently to allow it to set into an amorphous non-crystalline glass form (Form-II) of azithromycin having relatively increased solubility without decreasing the structural stability thereof.

INTRODUCTION AND BACKGROUND TO THE INVENTION

This invention relates to a macrolide composition. More particularlythis invention relates to a novel amorphous form, of(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside orazithromycin. This invention further relates to a preparation method ofa medicament. More particularly this invention relates to a method ofincreasing the solubility of azithromycin.

Azithromycin is an azalide and a member of the macrolide family ofantibiotics. This 15-membered-ring, macrolide antibiotic, is verysimilar in composition, chemical structure (semi-synthetic) andmechanism of action to erythromycin. Polymorphs of azithromycin commonlypresent as anhydrous (MM=749.00 g/mol), monohydrate (MM=767.02 g/mol) ordihydrate (MM=785.02 g/mol) azithromycin. It should however be notedthat azithromycin is acid-stable in 0.1 N HCl and that the dihydrate iscurrently the most stable polymorphic form.

The chemical formula for azithromycin dihydrate is C₃₈H₇₂N₂O₁₂.2H₂O andthe chemical structure of anhydrous azithromycin differs fromerythromycin through methyl-substitution of a nitrogen atom in thelactone ring.

The preparation of some amorphous forms of azithromycin has previouslybeen described in U.S. Pat. Nos. 6,245,903 and 6,451,990.

U.S. Pat. No. 6,245,903 describes an anhydrous form of azithromycin andfurther provides a method to purify an amorphous anhydrous azithromycinform using a chromatographic procedure or by using a solvent evaporationmethod.

U.S. Pat. No. 6,451,990 describes a non-crystalline form of azithromycinwhich includes the preparation method of forming a solution ofazithromycin and an aliphatic alcohol or cyclic ethers and lyophilisingsaid solution.

All non-crystalline forms of azithromycin referred to above aremanufactured using solvents and/or lyophilisation. Although theaforesaid methods are well-known in the pharmaceutical industry for thepreparation of different forms of a drug there are several disadvantageswith these known methods. Some of the disadvantages are that the methodsare time-consuming and require reagents for manufacturing. Yet a furtherdisadvantage associated with these methods is that the solvents in thestructure of the non-crystalline azithromycin can influence thephysico-chemical properties of azithromycin.

Azithromycin has an anti-bacterial spectrum parallel to erythromycin'sspectrum. It is however more effective against Haemophilus influenzaeand other gram-negative bacteria, including Staphylococcus aureus;Streptococcus agalactiae; Streptococcus pneumoniae; Streptococcuspyogenes; Haemophilus ducreyi; Moraxella catarrhalis; Neisseriagonorrhoeae; Chlamydia pneumoniae; Chlamydia trachomatis; Mycoplasmapneumoniae; Helicobacter pylori; Salmonella typhi; and Mycobacteriumavium intracellulare.

A disadvantage associated with known commercially available azithromycindihydrate (raw material) is that it is poorly soluble in water.

A further disadvantage associated with azithromycin is that its poorwater-solubility influences other pharmacokinetic properties resultingin the poor bioavailability (only 38% of an orally administered dosereaches systemic circulation) of the active drug.

Yet another disadvantage of azithromycin is that said poorbioavailability necessitates the administration of relatively largequantities of azithromycin in order to achieve the desired therapeuticeffect.

A disadvantage associated with the use of relatively large quantities ofazithromycin is that there is a potential increase in the side-effectsassociated with this active ingredient, in turn leading to poor patientcompliance and potentially resulting in bacterial drug-resistance.

An even further disadvantage associated with the use of relative largequantities of azithromycin is that there is an increase in theproduction and manufacturing cost of the product, thereby increasing thecost of treatment.

OBJECTS OF THE INVENTION

An object of the present invention is to provide a stable novel form ofazithromycin. Another object of the invention is to provide a method forincreasing the solubility of azithromycin. Yet another object of theinvention is to provide a medicament prepared in accordance with such amethod with which the aforesaid disadvantages may be overcome or atleast minimised.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided acomposition comprising a stable amorphous non-crystalline glass form(Form-II) of azithromycin.

The amorphous non-crystalline glass form (Form-II) of azithromycin maydisplay an infra-red pattern having a relatively broad peak atapproximately 3500 and 1727 cm⁻¹ and at least one characteristic peak atapproximately 2970 and 2938 cm⁻¹. The infra-red pattern may besubstantially depicted as in FIG. 2.

The amorphous non-crystalline glass form (Form-II) of azithromycin maydisplay a differential scanning calorimetry thermogram substantially asdepicted in FIG. 12 and exhibits a glass transition between 100 and 115degrees Celsius.

The amorphous non-crystalline glass form (Form-II) of azithromycin mayhave at least 50%, preferably at least 150%, increased solubilityrelative to anhydrous, monohydrated or dihydrated azithromycin in water.

The amorphous non-crystalline glass form (Form-II) of azithromycin mayhave at least 5%, preferably at least 10%, increased solubility relativeto anhydrous, monohydrated or dihydrated azithromycin in 0.1 Nhydrochloric acid (pH 1).

The amorphous non-crystalline glass form (Form-II) of azithromycin mayhave at least 10%, preferably at least 20%, increased solubilityrelative to anhydrous, monohydrated or dihydrated azithromycin inphosphate buffer (pH 6.8).

According to a second aspect of the invention there is provided a methodof increasing the solubility of azithromycin including the steps of:

-   -   providing azithromycin selected from the group consisting of        anhydrous, monohydrated or dihydrated azithromycin;    -   elevating the temperature of the azithromycin to above the        melting point thereof; and    -   reducing the temperature of the melt sufficiently to allow it to        set into an amorphous non-crystalline glass form (Form-II) of        azithromycin having relatively increased solubility without        decreasing the structural stability thereof.

The step of elevating the temperature of the azithromycin to above itsmelting point includes the step of elevating the temperature thereof tobetween 100 and 140 degrees Celsius, preferably 130 degrees Celsius, inthe absence of a solvent.

The temperature of the selected azithromycin is elevated to above itsmelting point in the absence of a solvent.

According to a third aspect of the invention there is provided amedicament prepared from anhydrous, monohydrated or dihydratedazithromycin in accordance with the method of the second aspect of theinvention.

According to a fourth aspect of the invention there is provided use of apharmaceutically effective amount of an amorphous non-crystalline glassform (Form-II) of azithromycin in accordance with the first aspect ofthe invention and prepared in accordance with the method of the secondaspect of the invention in a method of treating a patient suffering frombacterial infections.

According to a fifth aspect of the invention there is provided use of apharmaceutically effective amount of an amorphous non-crystalline glassform in accordance with the first aspect of the invention and preparedin accordance with the method of the second aspect of the invention in amethod of preparing a medicament for use in treating a patient sufferingfrom bacterial infections.

According to a sixth aspect of the invention there is provided a methodof treating a patient suffering from bacterial infections including thestep of administering to such a patient a pharmaceutically effectiveamount of an amorphous non-crystalline glass form (Form-II) ofazithromycin in accordance with the first aspect of the invention andprepared in accordance with the method of the second aspect of theinvention.

According to yet another aspect of the invention there is provided amedicament prepared from amorphous non-crystalline glass form (Form-II)of azithromycin in accordance with the method of the second aspect ofthe invention, together with at least one inert pharmaceuticallyacceptable carrier or diluents in the dosage form selected from thegroup consisting of tablets; capsules; powders; solutions; syrups;suspensions; bolus injection; continuous infusion; powder forreconstitution; enemas; douche; pessary; transdermal patch; dermalpatch; ointments; creams; gels; lotions; sprays and lozenges.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described further, by way of example only,with reference to the accompanying drawings wherein:

FIG. 1: is an infra-red (IR) pattern of prior art azithromycin dihydrate(Vertical axis: transmittance (percentage); Horizontal axis: wavenumbers(cm⁻¹)); (The infra-red pattern was obtained on a Shimadzu IRPrestige-21(Japan), using a Pike Multi-Reflectance ATR accessory, with ShimadzuIRsolution version 1.40 software. Pattern was recorded over a range of400-4000 cm⁻¹. KBr was used as background. The sample was dispersed in amatrix of powdered potassium bromide and, through diffuse reflectanceinfra-red Fourier transform spectroscopy (DRIFTS), the IR-spectrum wasmeasured in a reflectance cell.);

FIG. 2: is an IR pattern of amorphous non-crystalline glass form(Form-II) of azithromycin according to the invention (Vertical axis:transmittance (percentage); Horizontal axis: wavenumbers (cm⁻¹));

FIG. 3: is a characteristic XRPD (x-ray powder diffraction pattern) ofprior art azithromycin dihydrate raw material (Vertical axis: intensity(Lin (counts)); Horizontal axis: 2 Theta (degrees)); (Obtained on aPANalytical Xpert-Pro, Goniometer=PW3050/60 (Theta/Theta); Minimum stepsize 2Theta: 0.001; Measurement Temperature [° C.]: 25.00, AnodeMaterial: Cu, K-Alpha1 [Å]: 1.54060, K-Alpha2 [Å]: 1.54443, K-Beta [Å]:1.39225, K-A2/K-A1 Ratio: 0.50000, Generator Settings: 45 mA, 40 kV,Diffractometer Type: 0000000011018023, Goniometer Radius [mm]: 240.00,Dist. Focus-Diverg. Slit [mm]: 91.00, Incident Beam Monochromator: No,Spinning: Yes);

FIG. 4: is a characteristic XRPD (x-ray powder diffraction pattern) ofamorphous non-crystalline glass form (Form-II) of azithromycin (Verticalaxis: intensity (Lin (counts)); Horizontal axis: 2 Theta (degrees));

FIG. 5: is a characteristic XRPD (x-ray powder diffraction pattern) ofamorphous non-crystalline glass form (Form-II) of azithromycin takenover a period of time wherein 0 is at time of preparation, 1 is week 1,2 is week 2, 3 is week 3 and 4 is week 4 (Vertical axis: intensity (Lin(counts)); Horizontal axis: 2 Theta (degrees));

FIG. 6: is a solubility profile comparing the solubility of prior artazithromycin dihydrate raw material and amorphous non-crystalline glassform (Form-II) of azithromycin in water (Vertical axis: concentration(mg/mL); Horizontal axis: azithromycin form);

FIG. 7: is a solubility profile comparing the solubility of prior artazithromycin dihydrate raw material and amorphous non-crystalline glassform (Form-II) of azithromycin in 0.1 N HCl (Vertical axis:concentration (mg/mL); Horizontal axis: azithromycin form);

FIG. 8: is a solubility profile comparing the solubility of prior artazithromycin dihydrate raw material and amorphous non-crystalline glassform (Form-II) of azithromycin in Phosphate buffer (Vertical axis:concentration (mg/mL); Horizontal axis: azithromycin form);

FIG. 9: is a solubility profile comparing the solubility of prior artazithromycin dihydrate raw material in different mediums (Vertical axis:concentration (mg/mL); Horizontal axis: medium);

FIG. 10: is a solubility profile comparing the solubility of amorphousnon-crystalline glass form (Form-II) of azithromycin in differentmediums (Vertical axis: concentration (mg/mL); Horizontal axis: medium);

FIG. 11: is a DSC (differential scanning calorimetry) trace of prior artazithromycin dihydrate raw material taken over a period of time wherein1 is week 0, 2 is week 2 and 3 is week 4 (Vertical axis: Heat flow (mW);Horizontal axis: temperature (degrees Celsius)); (DSC trace obtained ona Shimadzu DSC-60A (Japan) with TA60 version 2.11 software.Approximately 2 to 4 mg of each sample was weighed and heated in openaluminium crucibles. Samples were heated at 2° C./min in an inertnitrogen atmosphere.)

FIG. 12: is a DSC (differential scanning calorimetry) trace of amorphousnon-crystalline glass form (Form-II) of azithromycin, taken over aperiod of time, according to one embodiment of the invention wherein 0is at time of preparation, 1 is week 1, 2 is week 2, 3 is week 3 and 4is week 4 (Vertical axis: Heat flow (mW); Horizontal axis: temperature(degrees Celsius));

FIG. 13: is a thermal microscopy image (at 25 degrees Celsius) ofamorphous non-crystalline glass form (Form-II) of azithromycin taken inthe fourth week after preparation according to one embodiment of theinvention; and

FIG. 14: is a thermogravimetric analysis (TGA) trace overlay ofamorphous non-crystalline glass form (Form-II) of azithromycin duringstability study (Vertical axis: Weight (mg); Horizontal axis:temperature (degrees Celsius)); (Obtained on a Shimadzu DTG-60 (Japan)with TA60 version 2.11 software. Samples were heated from 25 degreesCelsius to 150 degrees Celsius at 2° C./min, in open aluminiumcrucibles. Nitrogen gas was used as inert atmosphere.).

DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

According to a preferred embodiment of the invention there is provided amethod for increasing the solubility of azithromycin, by providing astable amorphous non-crystalline glass form (Form-II) of azithromycin.

The method includes the steps of selecting azithromycin from the groupconsisting of anhydrous, monohydrated or dihydrated azithromycin;elevating the temperature of the azithromycin to above the melting pointthereof; and reducing the temperature of the melt sufficiently to allowit to set into an amorphous non-crystalline glass form (Form-II) ofazithromycin having relatively increased solubility.

Further Details of Respective Steps in the Method According to theInvention:

The first step of the method, according to a preferred embodiment of theinvention is to select azithromycin raw material from known commerciallyavailable anhydrous, monohydrate or dihydrated form.

The following step of the method is to place the azithromycin rawmaterial in a suitable container, in the absence of any solvents, andheat it to approximately 130 degrees Celsius in a dry heat oven andafterwards cooling the melt to room temperature (25 degrees Celsius).

Alternatively, the azithromycin raw material can be placed in a suitablecontainer and heated in any suitable environment to approximately 130degrees Celsius. The melt is then cooled to room temperature (25 degreesCelsius).

Further Analysis and Findings

It has surprisingly been found that the amorphous non-crystalline glassform (Form-II) of azithromycin is structurally stable and significantlymore soluble in water, phosphate buffer and 0.1 N hydrochloric acidcompared to conventional anhydrous, monohydrate or dihydratedazithromycin prepared according to prior art methods.

In further analysis of the amorphous non-crystalline glass form(Form-II) of azithromycin, each of five replicate test tubes were filledwith an excess of amorphous non-crystalline glass form (Form-II) ofazithromycin and 10 ml of solubility medium. The process was performedwith each of the following mediums: 0.1 N hydrochloric acid (pH 1),acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and distilled water.This method was also used for testing the prior art azithromycindihydrate.

The test tubes were then fixed to a rotating axis (54 rpm) and submergedin a water bath at 37 degrees Celsius±2 degrees Celsius for twenty-fourhours. The contents of the test tubes were filtered through a 0.45 μmfilter and the respective filtrates were subsequently diluted.

The concentrations of the filtrates were determined by HPLC (highperformance liquid chromatography) assay. The HPLC assay was performedutilising a mobile phase (600:400) consisting of 8.7 g/L potassiumdihydrogen phosphate buffer (pH 4.5) and acetonitrile. A Luna C18 250mm×4.6 mm column was used with a flow rate of 0.5 mL/min and awavelength of 210 nm. Validation of this method provided a linearregression r² of 0.9999.

Referring to FIGS. 6 to 10, it was determined that the solubility ofazithromycin raw material (dihydrate) is 17.966±0.113 mg/mL in acetatebuffer (pH 4.5), 8.442±0.069 mg/mL in phosphate buffer (pH 6.8),40.814±0.368 mg/mL in 0.1N HCl and 0.148±0.028 mg/mL in distilled water.The phosphate buffer consists of potassium dihydrogen phosphate, sodiumhydroxide and water and the acetate buffer consists of sodium acetatetrihydrate, glacial acetic acid and water. It was further determinedthat the solubility of amorphous non-crystalline glass form (Form-II) ofazithromycin is 18.045±0.485 mg/mL in acetate buffer (pH 4.5),10.968±0.182 mg/mL in phosphate buffer (pH 6.8), 45.703±0.917 mg/mL in0.1 N HCl and 1.357±0.233 mg/mL in distilled water. In fact, incomparison with the raw material, amorphous non-crystalline glass form(Form-II) of azithromycin has a 9.16 fold (816%) improvement insolubility in water (FIG. 6), a 1.3 fold (30%) improvement in pH 6.8phosphate buffer and a 1.12 fold (12%) improvement in 0.1 N HCl (FIG. 7)as medium. It was found that the amorphous non-crystalline glass form(Form-II) of azithromycin is at least 50%, more particularly at least150% more soluble than anhydrous, monohydrated or dihydratedazithromycin in water. It was further found that the amorphousnon-crystalline glass form (Form-II) of azithromycin is at least 5%more, particularly at least 10% more soluble than dihydratedazithromycin in a 0.1 N HCl medium. It was yet further found that theamorphous non-crystalline glass form (Form-II) of azithromycin is atleast 10% more, particularly at least 20% more soluble than dihydratedazithromycin in a phosphate buffer medium.

FIG. 3 shows a characteristic XRPD pattern of the raw materialazithromycin and confirms that the azithromycin is in a crystallineform. This is in contrast to the amorphous non-crystalline glass form(Form-II) of azithromycin (FIG. 4) which exhibits the characteristicamorphous halo generally obtained with amorphous forms.

Referring to FIGS. 1 and 2, the infra-red (IR) pattern wavenumbersassociated with peaks for both the raw material (FIG. 1) and theamorphous non-crystalline glass form (Form-II) of azithromycin (FIG. 2)can be summarised as follow:

Azithromycin dihydrate Azithromycin glass 3567 and 3496 cm⁻¹ (Sharppeaks) 3500 cm⁻¹ (Relatively broad peak) 3251 cm⁻¹ (Relatively broadpeak) No peak 2971 cm⁻¹ 2970 and 2938 cm⁻¹ 1720 cm⁻¹ (Sharp peak) 1727cm⁻¹ (Relatively broad peak)

The most distinguishing difference between the IR patterns of the rawmaterial (FIG. 1) in comparison with the IR pattern obtained for theamorphous non-crystalline glass form (Form-II) of azithromycin (FIG. 2)lies between wavenumbers 3580 to 1727 cm⁻¹.

The IR pattern of azithromycin dihydrate (FIG. 1) displays peaks ofinterest at wavenumber 3600 to 3000 cm⁻¹. These peaks represent thehydrate (two water molecules) found in the structure of azithromycindihydrate. In contrast, FIG. 2 displays only one broad peak atwavenumber 3500 cm⁻¹ and no peak at 3251 cm⁻¹, which indicates a lack ofhydrated molecules in the amorphous non-crystalline glass form (Form-II)of azithromycin.

The IR-pattern of the raw material (FIG. 1) displays five separate,clearly distinguishable peaks at 3567, 3496, 3251, 2971 and 1720 cm⁻¹.This is in contrast to the amorphous non-crystalline glass form(Form-II) of azithromycin which display peaks at 3500 (broad peak),2970, 2938 and 1727 (broad peak) cm⁻¹.

The applicant established that amorphous non-crystalline glass form(Form-II) of azithromycin is structurally stable (at 40° C. and 75%relative humidity) over a period of time and remained amorphous as shownin the XRPD pattern (FIG. 5). In FIG. 5 the amorphous non-crystallineglass form (Form-II) of azithromycin displayed the characteristicamorphous halo generally obtained with amorphous forms over the 4 weektesting period. In FIG. 13 it was further evident from the micrograph ofthe amorphous non-crystalline glass form (Form-II) of azithromycin thatForm-II did not transform to a crystalline solid form of azithromycinbut remained non-crystalline.

Referring to FIG. 11, the DSC (differential scanning calorimetry) traceof prior art azithromycin dihydrate illustrates the two desolvationpeaks of the dihydrate between 80 degrees Celsius and 100 degreesCelsius and further illustrates a melting point at 119 degrees Celsiusto 121 degrees Celsius. In contrast to FIG. 11, FIG. 12 shows thethermogram of amorphous non-crystalline glass form (Form-II) ofazithromycin and depicts the absence of the two desolvation peaksbetween 80 degrees Celsius and 100 degrees Celsius and further displaysa glass transition between 100 degrees Celsius and 115 degrees Celsius.

The stability tests indicate that the amorphous non-crystalline glassform (Form-II) of azithromycin remained structurally stable as anamorphous non-crystalline form.

The thermogravimetric analysis (TGA) trace of FIG. 14 illustrates theweight loss of amorphous non-crystalline glass form (Form-II) ofazithromycin over a period of time. The TGA, together with the KarlFischer titration, results (averaging 3 to 4%) indicate the presence ofwater in the amorphous azithromycin. It is submitted that the presenceof water did however not influence the solubility or structuralstability of amorphous azithromycin in any way.

Amorphous non-crystalline glass form (Form-II) of azithromycin isformulated for administration in any convenient way and the inventionincludes within its scope pharmaceutical compositions comprisingamorphous non-crystalline glass form (Form-II) of azithromycin adaptedfor use in human or veterinary medicine.

The pharmaceutical compositions are presented for use in a conventionalmanner with the aid of a pharmaceutically acceptable carrier orexcipient and may also contain, if required, other active ingredients.The amorphous non-crystalline glass form (Form-II) of azithromycin istypically formulated for oral, buccal, topical or parenteraladministration.

Oral administration is the preferred dosage form, particularly in theform of tablets and capsules. The pharmaceutical composition for oraladministration conveniently takes the form of tablets, capsules,powders, solutions, syrups or suspensions prepared by conventional meanswith acceptable excipients. Buccal administration compositions take theform of tablets or lozenges formulated in conventional manner.

The amorphous non-crystalline glass form (Form-II) of azithromycin isfurther formulated for parenteral administration by bolus injection orcontinuous infusion. Formulations for injection are presented in unitdosage forms in ampoules, or in multi-dose containers, with an addedpreservative. The compositions further take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient is in powder form forreconstitution with a suitable vehicle.

The amorphous non-crystalline glass form (Form-II) of azithromycin isyet further formulated in topical applications, comprising ointments,creams, gels, lotions, powders; transdermal patches, dermal patches orsprays prepared in a conventional manner.

The particulate unsolvated anhydrous form of nevirapine (Form-I) is yetfurther formulated in rectal and vaginal compositions such assuppositories or retention enemas containing conventional suppositorybases such as cocoa butter or other glycerides.

For oral administration a convenient daily dosage regime of amorphousnon-crystalline glass form (Form-II) of azithromycin is a total of 200mg to 500 mg per day for three days, dependent upon the age andcondition of the patient.

The amorphous non-crystalline glass form (Form-II) of azithromycinprepared in accordance with the method of the present invention isformulated into a medicament and used in a method of treating a patientsuffering from a bacterial infection by administering to such a patienta pharmaceutically effective amount thereof of a total of 200 mg to 500mg per day for three days, dependent upon the age and condition of thepatient.

It will be appreciated that the disadvantages associated with prior artforms of azithromycin, namely anhydrous, monohydrate of dihydrate forms,could be alleviated with the method according to the invention. Inparticular, the bioavailability of azithromycin could be increased as aresult of the increased solubility of amorphous non-crystalline glassform (Form-II) of azithromycin. Moreover, reduced quantities ofamorphous non-crystalline glass form (Form-II) of azithromycin would berequired in use in treating patients suffering from bacterialinfections, resulting not only in reduced risk to side-effects but to areduced cost in treatment. Yet further, the advantages associated withthe preparation of Form-II is done in the absence of any solvent, thisbeing more cost-effective and less time consuming than known prior artmethods.

Applicant thus foresees that amorphous non-crystalline glass form(Form-II) of azithromycin would not only present a relatively cheaperalternative to conventional production and manufacturing methods, butwould also present a product that is superior in solubility toconventional anhydrous, monohydrate or dihydrate forms of azithromycin.

It will be appreciated further that variations in detail are possiblewith a method for preparing a medicament and a medicament prepared withsuch a method, according to the invention without departing from thescope of this disclosure.

1. A composition comprising an amorphous non-crystalline glass form(Form-II) of azithromycin.
 2. A composition according to claim 1 whereinthe amorphous noncrystalline glass form (Form-II) of azithromycindisplays an infra-red pattern having a characteristic relatively broadpeak at approximately 3500 and 1727 cm^(″1) and characteristic peaks2970 and 2938 cm^(″1).
 3. A composition according to claim 1 wherein theamorphous non-crystalline glass form (Form-II) of azithromycin displaysan infra-red pattern substantially as depicted in FIG.
 2. 4. Acomposition according to claim 1 displaying a differential scanningcalorimetry thermogram substantially as depicted in FIG. 12 andexhibiting a glass transition between 00 and 115 degrees Celsius.
 5. Acomposition according to claim 1 having at least 50% increasedsolubility over anhydrous, monohydrated or dihydrated azithromycin inwater.
 6. A composition according to claim 5 having at least 150%increased solubility over anhydrous, monohydrated or dihydratedazithromycin in water.
 7. A composition according to claim 1 having atleast 5% increased solubility over anhydrous, monohydrated or dihydratedazithromycin in 0.1 N HCl.
 8. A composition according to claim 7 havingat least 10% increased solubility over anhydrous, monohydrated ordihydrated azithromycin in 0.1 N HCl.
 9. A composition according toclaim 1 having at least 10% increased solubility over anhydrous,monohydrated or dihydrated azithromycin in a phosphate medium.
 10. Acomposition according to claim 9 having at least 20% increasedsolubility over anhydrous, monohydrated or dihydrated azithromycin in aphosphate medium.
 11. A method of increasing the solubility ofazithromycin including the steps of providing azithromycin selected fromthe group consisting of anhydrous, monohydrated or dihydratedazithromycin; elevating the temperature of the azithromycin to above themelting point thereof; and reducing the temperature of the meltsufficiently to allow it to set into an amorphous non-crystalline glassform (Form-II) of azithromycin having relatively increased solubilitywithout decreasing the structural stability thereof.
 12. A methodaccording to claim 11 wherein the step of elevating the temperature ofthe azithromycin to above its melting point includes the further step ofelevating the temperature thereof to between 100 and 140 degreesCelsius, preferably 130 degrees Celsius.
 13. A method according to claim11 wherein the temperature of the selected azithromycin is elevated toabove its melting point in the absence of a solvent.
 14. A medicamentprepared from anhydrous, monohydrated or dihydrated azithromycin inaccordance with the method of claim
 11. 15. A medicament prepared fromamorphous non-crystalline glass form (Form-II) of azithromycin inaccordance with the method of claim 11 together with at least one inertpharmaceutically acceptable carrier or diluents in a dosage formselected from the group consisting of tablets; capsules; powders;solutions; syrups; suspensions; bolus injection; continuous infusion;powder for reconstitution; ointments; creams; gels; lotions; spraysenemas, douche, pessary, transdermal patches, dermal patches andlozenges.
 16. Use of a pharmaceutically effective amount of an amorphousnoncrystalline glass form (Form-II) of azithromycin according to claim 1and prepared in accordance with the method of claim 11 in a method oftreating a patient suffering from a bacterial infection.
 17. Use of apharmaceutically effective amount of an amorphous noncrystalline glassform according to claim 1 and prepared in accordance with the method ofclaim 11 in a method of preparing a medicament for use in treating apatient suffering from a bacterial infection.
 18. A method of treating apatient suffering from bacterial infections including the step ofadministering to such a patient a pharmaceutically effective amount ofan amorphous non-crystalline glass form (Form-II) of azithromycinprepared in accordance with the method of claim
 11. 19. A compositioncomprising an amorphous non-crystalline glass form (Form-II) ofazithromycin substantially as herein described and exemplified withreference to the accompanying figures.
 20. A method of increasing thesolubility of azithromycin substantially as herein described andexemplified, with reference to the accompanying figures.